Kent Remington, MD

Dr Remington began the filler session with a discussion on facial reflation and the concept of aesthetics. For many years, we focused on the old aesthetic rule of “if it ain’t broke, don’t fix it.” The new rule in aesthetics is “if it ain’t broke, break it, then fix it and make it better.”

Dr Remington presented the audience with some key pearls and takeaway messages from his clinical experience.

**It is extremely important that dermatologists focus on the face in great detail as patients are paying for great results. One of Dr Remington’s biggest challenges is getting is patients to look at their entire face, as opposed to focusing on what they choose to see; therefore, missing a lot of things. “We look with our eyes and see with our brains.” By understanding and seeing everything about each patient, the outcomes can be better. It’s all about harmony and symmetry.

What do we need to think about in detail?

• Genetics
• Age group
• Personality and lifestyle
• Attention to details

Overall, faces are all about genetics, which are all about biology, which is all about physiology, which is all about physics, which is all about math; therefore, every face has a mathematical transformation. Dr. Remington presented a series of cases in which he used numerous fillers and neuromodulators to achieve an overall “reflation “of the face. In doing so he stated that it is not about the number of cc’s of material injected but more about what is needed to create a “wow”.

As dermatologists, we need to take a more comprehensive approach.  Instead of just injecting a specific area, step back and see what the patient really needs.

Where are we now?

Wm. Philip Werschler, MD

In this presentation, Dr Werschler provided the audience an overview of the fillers currently available on the market by class and by product, and how they can best be utilized in clinical practice.

How did we get here today?

Beginning in 1981, bovine collagen was introduced to the US marketplace. As people began to get their winkles and fold augmented to look younger they discovered that unfortunately, the duration of collagen was only three months or so, thus the market for collagen injections never grew to meet expectations   It was subsequently withdrawn from the market. In December, 2003, the US FDA approved Restylane (Hyaluronic Acid), which revolutionized the dermal filler market. With Restylane physicians a dermal filler that had a duration of over 6 months, required no pre-treatment skin testing, was easy to use,  could be stored at room temperature and had a modest cost.  With Restylane we had the introduction of a viable product for the emerging, if nascent, dermal filler market.

Radiesse is a novel “next-generation” filler that was approved in 2006 by the FDA for the correction of wrinkles and folds (such as Nasolabial Folds), and for the correction of HIV-associated lipoatrophy. Radiesse is termed a “stimulatory” or “collagen-stimulator” product.  This differs from the previous generation “replacement” space occupying materials collagen and hyaluronic acid.  With the addition of collagen stimulation, the duration of effect of Radiesse was extended to 9-18 months.

On the same day that Radiesse was approved, the FDA also approved the first and only “permanent” dermal filler, Artefill (collagen + PMMA).  Artefill consists of bovine collagen in combination with polymethmethacrylate spheres.   As these spheres are non-biodegradable, they represent a permanent placement into the tissue.  Well tolerated with an excellent safety profile, Artefill does require pre-treatment skin testing because of the bovine collagen present. Special handling includes refrigeration, and collagen stimulation gradually anchors the PMMA spheres into place typically after 2-3 treatments.

In 2007/2008 Hyaluronic Acid plus manufacturer added lidocaine was FDA approved for the hyaluronic acids, Juvederm, Restylane and Perlane. Similarly, the FDA approved the mixing of lidocaine and Radiesse by the injector at the time of use.  These approvals resulted in greater patient comfort during injection and further expanded the dermal filler marketplace. Stabilized Porcine Collagen came onto the market briefly during this time, however due to problems with patient tolerance and complications, the manufacturer withdrew the product and it is no longer available.

In 2009, the FDA approved Sculptra, poly-L -lactic acid, for aesthetic use (it received FDA approval in 2004 for HIV associated facial lipoatrophy).  A pure collagen stimulator, Sculptra, is technically is not a dermal filler, however; it is best thought of in this category.  Sculptra is routinely mixed with lidocaine and sterile water for injection, requires 3-5 injections sessions to gradually grow new collagen leading to the clinical effect developing over a period of three to six months.  Duration is a 2+ years effect based on extensive clinical trials and experience.

More recently, an advanced technology hyaluronic acid, Belotero, and  an autologous cultured dermal fibroblast  (LAVIV)  were approved. Belotero is a “cohesive polydensified matrix” hyaluronic acid that possesses different tissue integration properties than previous generation products.  The net clinical result is that the product may be injected more superficially than other HAs without risk of the Tindall or Rayleigh effect tinting the skin blue.

Laviv, is not a dermal filler but instead uses a patients own fibroblasts which are harvested from a punch biopsy, grown in a lab and then injected into the patient.  The injected fibroblast then produce native collagen in the patient’s skin  This process includes harvesting tissue from the patient (post-auricular) and sending it to a processing laboratory which then amplifies the cell count and returns a viable culture for re-injection. The first FDA approved tissue therapy for aesthetics, Laviv, presents a multitude of intriguing possibilities in the future.

Ever since fillers first came onto the market, experts have been trying to develop a methodology to differentiate one from another. There are many ways  to do so:

• Chemical components
• Duration of action
• Natural/Synthetic
• MOA
  • Replacement Filler or Bio-Stimulatory/collagen stimulator

Remember that fillers exist in two primary categories:

• Volume Replacement
• Collagen Stimulation

When you use the above descriptive methodology, you can see that collagen and hyaluronic acids are replacement fillers and PLLA and LAVIV are bio-stimulatory. And notably, CaHA and PMMA are blends of both MOAs.

There are many ways to categorize fillers within a class.

Volume Replacement

Hyaluronic Acid

HAs have a very simple chemical structure and is identical in all species and tissues; thus it is non-immunogenic. It is found in all vertebrates and synthesized by some bacteria. The identical structure of HA from all sources makes it an ideal substance for use as a biomaterial in health and medicine.  HAs are highly hydrophilic; therefore, they absorb water, i.e., their principal method of giving a volumizing effect. They are also rapidly metabolized in vivo.

Gel Mass Sizing

In addition to crosslinking, manufacturers use other techniques to improve HA filler properties.  For example, Medicis uses a process that creates specific sizes and shapes to form granular consistency gels Restylane^® and Perlane^®.

In creating the JUVÉDERM^® family of products, Allergan uses Hylacross™ Technology to create random sizes and shapes that form a smooth cohesive gel. Beletero, which is rather new to the market, uses another technology (CPM) to achieve unique properties.

Hyaluronic acids can be used virtually everywhere for anything and everything and they are the most versatile of all of the filler products. These fillers may be ideal for novice patients because they have an  “eraser” (hyaluronidase), which can be injected to make the product dissolve, if so desired for either aesthetic effect or for treatment of necrosis. . This is a unique feature of this category.

New Approaches to Fillers: Pure Neocollagenesis

PLLA

Through a variety of mechanisms of action, they stimulate fibroblasts to make collagen.

PLLA was first approved for HIV-related facial lipoatrophy in the United Sates in 2004 and the aesthetic approval was received in 2009.  It is the only approved pure collagen stimulator currently available in the US; therefore, it is considered “stimulatory” and “biodegradable” in classification. PLLA is indicated for the correction of nasolabial folds. Of note, Dermik aesthetics, a division of Sanofi-Aventis, recently sold the product to Valeant Pharmaceuticals Intl. based in Canada.

What is the composition of PLLA?

• Poly-L-lactic acid
• Sodium  carboxymethylcellulose (CMC)
• Non-pyrogenic mannitol
• Sterile water (added) for injection (USP)
• Lidocaine (optional—most dermatologists and plastic surgeons add lidocaine for patient comfort)

Sculptra is composed of microparticles of PLLA, a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family.  It is derived from natural components, it is a crystalline, amorphous mixture with microparticles averaging 40 to 63 μm in size. The slow resorption of PLLA after implantation is due to the high molecular weight (140,000 Daltons) of the polymer and the irregular crystalline shape of the microparticles.

Lactic acid can be converted through polymerization to a variety of polymers, including poly-L-lactic acid. Many of these polymers, including polylactic acid, have been used for many years in medical devices and sutures, including absorbable sealants, flow restrictors, fixation systems, suture anchors/absorbable sutures, fixation screws, and tissue regeneration.

Investigator evaluations throughout the study confirmed that improvements in facial appearance with Sculptra Aesthetic achieved improvement in WAS. 100% of patients improved at week 3; 88.7% at month 13; and 86.3% at month 25.

How long does it last? Sculptra may last two to three years. It is important to remember that it is difficult to establish exact duration of the product because of one’s natural course of aging.

Where is it used?

Poly-L-lactic acid treatment primarily to add volume, and as such is used to thicken dermis and to stimulate collagen growth in the pre-periosteal plane.  Placement may include the temporal hollows, across the zygomata, in the mid face, nasolabial folds, labiomental sulcus, pre-jowl sulcus, mandibular sweep, angle and for genioplasty.  Sculptra is not recommended for use in areas of concentric movement such as the lips and eyelids.  In terms of adding volume, this is a great way to go.

Personalized Dermal Technology

LaViv is an innovative technology to isolate, purify, and regenerate a patient’s own fibroblast cells for re-injection.

Fibroblast cells produce collagen and play key role in the continued health of skin. Collagen provides firmness and structure to the skin and is essential in supporting the dermis.. As skin ages, fibroblast cells decrease and the collagen matrix that provide the skin its structure breaks down.

This is a way to restore the equilibrium.  LaViv is the first autologous cell therapy for use in aesthetics filed with the FDA. There is strict release testing on each clinical lot to ensure performance and safety including:

• Collagen content testing results must achieve specification for each prepped injection, indicating cells are biologically active and produce collagen
• Cell suspension must consist of at least 98% fibroblasts prior to release
• Cells in suspension must achieve a viability level of at least 85%

New Approaches to Fillers: Volume Replacement + NeoCollagenesis

Calcium Hydroxylapatite (CaHa)-Radiesse

CaHa is best used for facial contouring. It’s mechanism of action is to serve as a filler material initially (particles + gel) then provide long term benefit through natural collagen integration in and around the particles. The result is a long lasting, but not permanent correction augmentation that feels like the patient’s own tissue.

The advantages of Radiesse include immediate site-specific correction in one to two sessions and strong structural tissue support with no Tyndall effect. CaHa is malleable up to two weeks and has a long duration of nine to 18 months. No pretreatment testing is required, it is also cost-effective and does not migrate or obscure radiographic studies and it doesn’t ossify in the skin. Radiesse received approval in the United Sates in 2006 for both HIV and aesthetic use and is the only approved biodegradable dual collagen stimulator and replacement filler currently available in the US. When utilizing Radiesse, no skin or allergy testing is needed and there is no special handling. The product is available in 0.3, 0.8 and 1.5 mL and recently approved 3.0 mL syringes through Merz Aesthetics.

Where is it used?

CaHA is used most everywhere; however, it is not ideally used in the lips or the eyelids. Some people do use the product in those areas; however, Dr Werschler does not recommend it.

PMMA Dermal Filler-Artefill

Artefill was approved in the United Sates in 2006 and is the only approved PMMA-enhanced dermal filler currently available in the US. It is indicated for the correction of nasolabial folds. Suneva Medical acquired (ARTES) Artefill in 2009 and is currently manufacturing, selling, and distributing Artefill in the US.

Conclusions

Injectables are: Facial Shaping Agents

• They can enhance natural features
• They can rejuvenate fading youth
• They can restore aged, facial features
• They can even improve natural beauty
• Each product has features that result in certain benefits in clinical use
• They are not all alike!

What’s new since last year?

• Belotero is “back” on market
• Valeant owns Medicis, Dermik
• Still waiting FDA approval for Allergan’s Voluma
• Artiste injection pump now available
• 2013 is still young!

Clinical Pearls

• Use filling agents appropriate to the requirements of the job
• Not all products are created equal – understand the differences!
• Some areas are more difficult to correct than others  (e.g. lips and tear troughs) so master the basic indications first such as NLF
• Evaluate and approach filling from a multi-step progression:
  • Volume, shape, contour, wrinkle, line and crinkle filling
  • Product duration claims are a slippery slope- be careful with those and be conservative with your ranges
  • Under-promise and over deliver

Botulinum Toxin 2013: Where are we now?

Joel Cohen, MD

It is important that clinicians understand the molecular structure of Botulinum neurotoxin type A. Botox and Dysport have an envelope of protein around it; xeomin; however, does not have these accessory proteins.

Differentiating Botulinum Toxins

Regulatory agencies worldwide have recognized that these products are not interchangeable. The units of biologic activity in each available product cannot be compared or converted into the units of any of the other available products, nor can the doses or preparations be interchanged. You need to learn how to use each product effectively.

New Data on Xeomin

In a head to head study comparing Xeomin to Botox for the treatment of cervical dystonia both products appear to be effective for this subset of patients.

What about the aesthetic use of Xeomin?

It’s important to note that the changes in FDA requirements over the fast few years are quite profound. The FDA now requires a two-grade improvement, whereas when Botox was conducting it’s clinical trials, the FDA only required a one-grade improvement. Overall, Xeomin and Botox appear to have similar efficacy.

Crow’s Feet

A small Xeomin study for the treatment of crow’s feet (N = 21) also demonstrated similar efficacy between both products.

Science and Data to Consider

We have very good safety and efficacy studies available. Patients seem to have a better quality of life, and look and seem happier. It is important to understand where not to inject. Over the last few years, we have seen success in treating crow’s feet and may begin to see more of a focus in this area. It’s imperative to look at each patient’s musculature when injecting toxins so as to achieve maximum results.

What’s new with botulinum toxin-A?

Combination Delivery

Dermatologists should be cautious of the dangers associated with delivering fillers and toxins simultaneously.

Zinc supplementation

A recent publication by Dr Koshy (April 2012) advocated the use of a proprietary zinc formulation to augment botulinum toxin efficacy for patients using toxins for aesthetic purposes. This paper presented many problems, mainly the fact that zinc augmentation of the botulinum toxin efficacy effect has never been described. And the actual study was done very poorly.  Where does the idea to use zinc come from?

The neuronal receptor for botulinum toxin is comprised of a heavy chain and light chain. A zinc dependent metalloprotease is responsible for cleaving the botulinum protein for it to be effective. The article (above) suggests that we are zinc deficient and; therefore, we don’t have enough zinc. This effect remains to be seen and we should be skeptical of this study.

Dosing

If we look specifically at dosing, data used to suggest that higher botulinum toxin type A doses resulted in greater efficacy and longer duration of the effect. In 2008, experts developed a consensus (rewrite from 2004) with regards to how to best achieve an optimal, relaxed and natural outcome using botulinum toxin type A. This resulted in basically cutting the forehead doses in half.

We have choices and dermatologists should review the various recommendations and guidelines in order to obtain the best effect for their patients.

Dueling

Patient satisfaction is a key aspect of facial aesthetics. Various studies have looked at patient reported outcomes among the products available; however, it is often difficult to compare the results.

Onset

With regards to the use of Dysport, when patients were asked, it seemed to work within a couple of days. No one recorded that information with Botox. In general, botulinum toxin type A begins to work in about two days.

Duration

Across the board, looking at the glabellar lines, the duration of botulinum toxin type A is about four months in about 50% of patients.  Data has also demonstrated that patients tend to have a cumulative effect; in that, the efficacy with repeated injections is extended over a longer period of time.

Joel Cohen, MD

In this presentation, Dr Cohen reviews the complications that can occur when utilizing fillers and best practices on how to manage these various complications. Dermatologists use fillers across the world, millions of times per year, and most of the time, everything is fine; but understanding the complications and how to manage them is imperative for us aesthetic dermatologists.

Clinicians should be aware that there are new filler agents and new indications for the agents currently available, so it is important to understand these products and recognize what can potentially go wrong when using them in our patients.

Filler complications include:

• Superficial injection
• Vascular compromise
• Bruising
• Sensitivity
• Granuloma
• Infection (or possible ” biofilm”)

Superficial Injection

When injecting the peri-ocular area, it is critical that dermatologists understand the anatomy and how to inject these areas.  When Dr Cohen injects these areas, he defines them by either “infra-orbital hollow” or “tear trough”.

Approach to Infra-Orbital Hollow injection

This is a much less common injection than the actual tear trough. Dr Cohen uses anesthetic eye drops, a jaeger retractor to protect the globe, and a 32 gauge needle above the level of the muscle. He discusses the importance of the 32 gauge needle as he believes it slows down the injection, or alternatively a 30g cannula can be used as well to try to decrease the incidence of bruising. This is an off-label area of injection and should be done very superficially, but it is very important to avoid superficial nodules—so inject slowly and avoid depositing clumps.

Injecting the Tear Trough

Dr Cohen injects very deep, below the muscle on the level of the periosteum. An anterior approach may help to lessen bleeding encounters.

Persistent Swelling

Persistent swelling has been documented across the board with various fillers. It is important to remember that this is an off-label area and dermatologists choose their agents based on personal preferences.  Experts are not sure if the swelling is related to etiology, e.g., Botox a few weeks prior. Treatment for persistent swelling includes time, massage, caffeine, oral HCTZ, and hyaluronidase.   Hyaluronidase can be helpful for an area that was superficially injected (very localized).

When injecting the glabella, you would want to see a little bleeding, you absolutely do not want to see it blanche.  Bototulinum toxin immobilization prior to filler (sometimes a week or two prior), may provide a better, more durable response with the filler (Carruthers, Derm Surg, 2003).

Vascular Compromise and Necrosis

The glabella is an area at significant risk for impending necrosis. Vascular compromise and necrosis, albeit rare, are caused by compression and intravascular injection.  In 2006, Dr Cohen and colleagues published a prevention and treatment protocol for injection necrosis of the glabella (Derm Surg, Feb 2006).

Understanding the facial arteries is of great importance for dermatologists who do soft tissue augmentation.

If you see a blanche, immediately stop the procedure. With some warm tap water gauze, try to tap the area and the warmth will facilitate vasodilation. If you have nitro paste in your office, you can apply that as well along with giving your patient aspirin to manage the headache associated with nitro paste.

Understanding the vessels and patterns is important not only to dermatologists, but to patients and office staff as well. Hyaluronidase with multiple stabs and perhaps into the adjacent artery has been demonstrated as a novel treatment for impending necrosis. It is very important as a healthcare provider to intervene immediately and not “wait and see what happens” in the cases of impending necrosis. A new article in Derm Surg suggests prostaglandin E may be helpful, and many experts also recommend hyperbaric oxygen be considered in some cases as well.

Scars

Fillers can be for postsurgical depressed scars on the ears, nose, and cheeks. Dr Cohen and colleagues published various case reports in 2008 on the use of fillers for postsurgical depressed scars after skin cancer reconstruction. The use of hyaluronic acid and calcium hydroxylapatite has proven successful to fill and blend these scars.

Bruising

Bruising may occur regardless of the injection site. The injection pattern is extremely important and it is critical that dermatologists understand the various approaches to injection. There are some things that patients can do to reduce bruising, such as avoiding non-therapeutic anticoagulant over-the-counter agents.. There are vitamins that can potentially interfere with bleeding; so again, something to keep in mind.  Clinicians need to be realistic with their patients, so they can expect some bruising and/or swelling which may last up to ten days. It is important to communicate this as a reality with patients prior to the procedure.

Cannulas

There are a few cannulas available in the US. Dr Cohen uses cannulas most often in the hands, cheeks, infra-orbital, and décolleté. They seem to decrease bruising along with potentially decreasing pain in some areas, and this has been seen in two preliminary studies (Hexsel and Barrone).

Summary

In conclusion, there are a variety of fillers available for patients. It is important that dermatologists understand the anatomy of the face in order to optimize injection results and minimize potential complications.

Michael Gold, MD

Dermatologists should be aware that the global medical aesthetic market is expected to grow 10.8% per year between 2010 an 2015 and many other companies are joining the toxin “band-wagon”.

Products Under Development/Currently Approved in Other Countries

• Medy-Tox – Neuronox (South American and Korea)
• Siax – Neuronox (Colombia)
• ChinaTox –Lanzhou Biological Products Institute, Nanfeng Medical  Science and Tech co.
• Lantox (South America)

Mentor is currently developing a product called PurTox, which is about one year away from filing with the FDA for approval. There are also several products currently available in Asia and South America. Dermatologist should recognize that in some instances where non-approved Botox formulations were used in the United States, patients required hospitalization due to paralysis and physicians were subject to major sanctions, fines, etc.

Summary

It is important that practitioners use branded products from legitimate companies that are either FDA approved in the US or CE marked in Europe, or received regulatory approvals in your country.  There are various unbranded products available on the internet; however, clinicians should use caution with regard to the use of these products due to safety and efficacy issues.

Joel Cohen, MD

In this presentation, Dr Cohen reviews the use of botulinum toxins in clinical practice. He reviews the three Type A toxins such as Botox, Dysport, and Xeomin.

Science and Data To Be Considered

It is important that clinicians understand the molecular structure of Botulinum neurotoxin type A.

The core neurotoxin protein in all agents used clinically is 150kD BoNT/A.  Botox and Dysport both have accessory proteins that surround the core neurotoxin, while Xeomin lacks accessory proteins.

Botulinum toxin Type A works via chemodenervation, in that the internalized toxin binds to the SNAP-25 target protein and then blocks the exocytosis of acetylcholine into the synaptic cleft following a neural impulse.  This effectively denervates the segment of muscle supplied by the affected cholinergic nerve terminal.

Differentiating Botulinum Toxins

Regulatory agencies worldwide have recognized that these products are not interchangeable. The units of biologic activity in each available product cannot be compared or converted into the units of any of the other available products, nor can the doses or preparations be interchanged.

Immunogenicity

Dermatologists should be aware that botulinum toxin itself could be immunogenic. The protein added to stabilize the product also has immunogenic properties. If antibodies occur, the question is whether or not they are neutralizing “critical domain” antibodies or non-neutralizing “non-critical domain” antibodies.  Antibody detection can measured through two tests. The Mouse Protection assay is the most widely used with the highest specificity. The patient’s serum is taken and given to a mouse. The mice are then given a lethal dose of BTX-A. If the mouse lives, the patient has antibody; in most cases the mouse would die. The rapid immunoassays (ELISA, W. BLOT) have a lower specificity and a lack of correlation between detected abs and clinical resistance.

Various data and studies suggest that overall, few patients may develop antibodies; however, they if they do develop antibody, they seem to continue to respond to the products.